Session: 201. Granulocytes, Monocytes, and Macrophages: Poster III
Hematology Disease Topics & Pathways:
immune cells, Cell Lineage
Single-cell RNA sequencing (scRNAseq) has shown that anti-CTLA-4 more effectively enhances cell cycle and effector memory pathways, while anti-PD-1 mostly enhances metabolism and effector function (Gubin et al., 2014). VISTA is a negative checkpoint regulator prominently expressed in the tumor microenvironment (TME) of a wide variety of cancers. In the CT26 preclinical model of colorectal cancer, monotherapy of small tumors (40 mm3) with a blocking anti-VISTA mAb (clone 13F3) markedly slowed tumor growth. Mice bearing large tumors (600mm3) all died despite anti-PD-1 and anti-CTLA4 mAb treatment, indicating checkpoint resistance. Inclusion of anti-VISTA led to complete rejection of 50% of tumors (Fig. 1). The underlying therapeutic mechanisms of enhanced anti-tumor immunity was investigated by high-dimensional scRNAseq of the CD45+ immune infiltrate 10 days after treatment initiation. In both settings, the mechanism of anti-VISTA impact on myeloid function was defined, with specific induction of myeloid signaling and antigen-presentation pathways. Suppression assays showed that the myeloid infiltrate was less suppressive to T cells. Multi-spectral imaging was used to characterize the distribution of infiltrating immune cells, and cell-cell contacts of immune cells were quantified. Along with unique transcriptional signatures, improved cellular interactions of anti-VISTA treated tumors supported increased antigen presentation.
Transcriptional analysis of tetramer-enriched tumor-specific CD8 T cells showed that anti-VISTA therapy induced T cell pathways highly distinct from the anti-exhaustion effects of anti-PD-1 therapy, contrasting the mechanisms of anti-VISTA with traditional checkpoint blockade.
These data document the unique and complementary impact of targeting VISTA in contrast to PD-1 and CTLA-4 in both the myeloid and T cell lineages. These mechanistic insights strongly support the use of anti-VISTA to overcome the checkpoint resistance seen in contemporary treatments involving PD-1.
Disclosures: Sarde: Amphivena Therapeutics: Current Employment, Current equity holder in private company. Blazar: Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; Tmunity: Other: Co-founder; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding; KidsFirst Fund: Research Funding. Noelle: Immunext: Current equity holder in private company, Patents & Royalties: 10035857, 9631018, 9217035, 8501915, 8465740, 8236304, 8231872, 9890215 and 9381244.
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